Intensified glycemic control is now recommended as the standard of care for all patients with diabetes. Unfortunately, the major barrier to achieving normoglycemia in patients with diabetes is hypoglycemia. Further complicating management of patients with diabetes is that the therapeutic cornerstone of exercise also contributes to increased hypoglycemia. Many studies have identified that intensive glycemic control can result in acquired failure of neuroendocrine and importantly autonomic nervous system (ANS) counterregulatory responses during hypoglycemia. Recent work has also demonstrated that episodes of both antecedent hypoglycemia and exercise can result in reciprocal, subsequent ANS counter regulatory dysfunction during either stress. The mechanisms responsible for prior hypoglycemia and/or exercise resulting in ANS counter regulatory dysfunction have yet to be determined. Recent interest has begun to be focused on central nervous system (CNS) regulation of physiologic responses during exercise and hypoglycemia. Currently, there are no adjunct treatments that protect the ANS from the deleterious effects of repeated episodes of hypoglycemia. In this application, we will propose therapeutic interventions aimed at reversing the central mechanisms that result in hypoglycemia associated autonomic dysfunction (HAAD). Atherothrombosis is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Recent large clinical trials have highlighted the association between hypoglycemia and increased mortality in T2DM. Of concern is the lack of information regarding the physiologic effects of ANS activation on endothelial function and atherothrombotic balance during hypoglycemia in diabetic individuals. Studies outlined in this proposal are therefore focused at determining the in-vivo mechanisms regulating ANS counter regulatory responses and in-vivo vascular and metabolic effects during hypoglycemia and exercise in healthy and diabetic humans. Experiments will use the glucose and pancreatic clamp techniques to control glucose levels and glucoregulatory hormones. ANS responses to hypoglycemia will be assessed by measuring circulating catecholamines, pancreatic polypeptide, muscle sympathetic nerve activity (MSNA), symptom scores and heart rate variability. Neuroendocrine responses will be determined by measuring growth hormone, Cortisol and glucagon levels. Metabolic counter regulatory mechanisms will be quantified by measuring glucose turnover, lipolysis and substrate oxidation via indirect calorimetry. Nitric oxide and non-nitric oxide dependent endothelial arterial function will be determined by flow mediated vasodilation, vascular atherothrombotic balance will be determined by PAl-1, TPA, P-selectin and adhesion molecule levels.